rs1060502089

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_003072.5(SMARCA4):c.964G>A(p.Ala322Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000969 in 1,445,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

SMARCA4
NM_003072.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.84

Variant links:

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.3971241).

BP6

Variant 19-10987770-G-A is Benign according to our data. Variant chr19-10987770-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408663.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 6 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 6 of 35	ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 6 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 6 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 6 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 7 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 6 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 6 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 7 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.376G>A	p.Ala126Thr	missense_variant	Exon 3 of 32			ENSP00000496004.1	A0A2R8YGG3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000143

AC:

AN:

209440

Hom.:

AF XY:

0.00000866

AC XY:

AN XY:

115518

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000313

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000352

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000969

AC:

AN:

1445430

Hom.:

Cov.:

AF XY:

0.00000697

AC XY:

AN XY:

717738

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000232

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000905

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

Cov.:

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2

Uncertain:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 322 of the SMARCA4 protein (p.Ala322Thr). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 408663). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Mar 16, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Hereditary cancer-predisposing syndrome

Benign:1

Apr 24, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.0068

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T

Eigen

Benign

0.082

Eigen_PC

Benign

0.088

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.40

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

1.4

L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.0

N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.22

T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T

Sift4G

Benign

0.44

T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T

Polyphen

0.98

D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D

Vest4

0.54

MutPred

0.17

Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);Gain of glycosylation at A322 (P = 0.002);

MVP

0.69

MPC

0.88

ClinPred

0.70

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over